Learn why timing is so important, particularly in rare disease

Rare disease drug development is growing, and in most cases, these diseases are often poorly understood by the scientific community and most lack any approved therapies. Optimizing rare disease interventional trials early in clinical development is critical to avoiding trial pitfalls by ensuring appropriate endpoints are measured and recruitment is successful through the selection of clinical sites and identification of patients. Natural history of disease studies can provide the foundation for optimized interventional trials, particularly in rare disease.

There are several benefits to conducting an early natural history of disease study:

1. Characterize rare disease or rare subtypes

Rare diseases are often not well understood, and thus accurate diagnosis, time to diagnosis, clinical manifestation, patient journey, and prognosis, among other key disease attributes, are usually lacking in scientific publications or understanding throughout the scientific community. A natural history of disease study can gather insights into the disease or subtypes of the disease ensuring the clinical development program includes the most appropriate patients and endpoints.

2. Plan your interventional trial and establish trial endpoints

Establishing the right trial endpoints maximizes the drug’s ability to demonstrate efficacy by ensuring we are measuring the aspects of the disease most likely to change. Natural history studies can be used to assess new or existing clinical outcomes to detect progression or patterns of disease collected from clinicians, directly from patients, or through the identification of biomarkers.  By conducting the natural history study ahead of the interventional trial, we can select the most appropriate endpoints based on disease evidence and work with regulatory bodies early to gain alignment. This is important, as choosing the wrong endpoints can be detrimental to the clinical development program.

When surrogate endpoints are needed, the natural history study can generate the evidence needed to show appropriate correlation between an endpoint, like overall survival, and surrogate endpoints, like biomarkers, to understand efficacy within a shorter time frame.

In addition, natural history insights are available in time for interventional trial protocol, statistical analysis plan, and study document development. Early natural history studies avoid the time and cost needed for amendments when these studies are run concurrently.  

3. Build relationships with sites and key opinion leaders (KOLs)

Building site and KOL relationships as part of the natural history study expedites site selection when it comes time for the interventional trial. The right sites can be difficult to locate for rare diseases; by ensuring we have relationships established ahead of time, we know which sites have eligible patients and are likely suitable to conduct an interventional trial. We can approach and engage with providers and KOLs early.

4. Engage patients ahead of interventional trial recruitment

Most rare diseases are without a treatment or cure, and patients’ interest to participate in a natural history study is usually to improve understanding in their disease community in the hopes of future treatments. By participating in the natural history study, patients can be screened ahead of the interventional trial for eligibility and engaged with quickly as to whether they want to participate and receive the study drug. This ensures patients are provided the option to access potentially life altering or saving medications faster. In addition, learnings from the natural history study can determine how best to facilitate patient participation in the interventional study where patient burden is higher.

5. Leverage operational efficiencies

When a natural history study is conducted ahead of the interventional trial, those operations can enable a smoother transition. For example: study-related documents, templates, and tools are shared across studies, site burden is reduced by using resources established for the natural history study in the interventional trial (e.g., Clinical Research Associates, project or program oversight, etc.), vendor start-up times are expedited (e.g., electronic data capture platform), and site insights like typical KOL response times and previously negotiated contract language are leveraged. Not only do these operational efficiencies reduce burden on the sponsor but on the sites and patients, as well.

When is the right time to start your natural history of disease study?

The above benefits are maximized by conducting your natural history study as early as possible in rare disease drug development, though value can be realized throughout your clinical program. We utilize scientific and methodological expertise and end-to-end solutions to maximize this value. 

• First, we bring in our medical team to assist in designing the study and protocol, with an eye to future interventional trials. We also strongly recommend working with patients or an advocacy group in upfront study planning 
• We then use a two-pronged approach to identify patients, first by leveraging sponsor relationships with specialists or patient advocacy groups, and second by using data to form patient density insights. The patient density insights de-risk site selection and identify additional difficult to find rare disease patients 
• Next, we consider a range of data capture methods. The use of secondary data or enriched data is important in rare disease to not only maximize eligible patients but to reduce burden on sites and patients 
• We then ensure timely reporting of key study results for interventional trial planning for regulatory discussions 
• Lastly, we use our experience engaging with regulators around natural history of disease studies to plan our engagements and seek alignment early on in clinical development. This is particularly relevant when the natural history study longitudinal data set is being considered for use as an external or historical comparator to a single-armed interventional trial

The evidence from both the data and the operations used during the natural history study can be leveraged to optimize interventional trials. Asking the right questions early in clinical development and working with teams who understand the unique needs within the rare disease space ensures sponsors understand the disease space upfront, avoiding interventional trial pitfalls, like selecting the wrong endpoints, down the line.

For more information about conducting your natural history of disease study, please reach out to cassie.holt@iqvia.com.